ALS Alert Newsletter | August

When the Conversation Fails

The search for a toxic factor from astrocytes

Astrocytes may release a toxin that advances ALS.

ALS neuroscientist Serge Przedborski co-directs the Center for Motor Neuron Biology and Disease at New York's Columbia University. He collaborates with Packard researchers in a common undertaking called P²ALS – a three-year, intensely-focused project involving ALS genetics, nervous system signaling and stem cell biology. Below, we summarize key points of a talk he gave at Packard's July Investigators' meeting.

Getting ALS is like loading a balance with small weights until it tips. That concept makes sense to researchers who believe that some combination of predisposing genes, an increasingly unfriendly internal cell chemistry and possibly something environmental work together to cause the shift from health to disease.

Investigators singly or collectively chip away at the problem, their studies making progress that's steady but rarely dramatic. New research in Serge Przedborski's lab, however, leans toward the latter, with clear potential for something significant.

The work Przedborski (pched BOR ski) reported centers on flaws in the way motor neurons and astrocytes, their close cell neighbors, interact. Astrocytes are the most abundant cells in the brain and spinal cord. They "converse" with neurons – including motor neurons – trading molecules that both sustain and protect each other. But this relationship presents a likely target in ALS, Przedborski says.

The problem isn't just that, in disease, astrocytes are less robust and can't sustain their end of the conversation. "Our recent study lets us believe, instead, that astrocytes make an active, primary contribution to the ALS process," he explains.

Przedborski's present studies point to a toxic mechanism at work.

To demonstrate that, his lab first cultured a single layer of pure astrocytes from ALS mice (they carry the familial mutant SOD1 gene). Then, healthy spinal cord neurons – sampled and purified from normal mouse embryos were layered atop the astrocytes. Within a short time, motor neuron survival rate plummeted. Conversely, neurons other than motor neurons stayed healthy.

In a telling step, the researchers extracted the nutrient medium from that experiment – all previous cells were filtered off – and added new neurons. They, too, died. "This suggests that astrocytes release a toxic agent into the medium," says Przedborski.*

A repeat of the study using a purer sample of motor neurons newly derived from human stem cells gave the same results.

Now the search is on to define the toxic agent. Using a variety of sophisticated techniques, Przedborski?s group has an idea of its molecular size and some of its properties, "but," he says, "we haven't yet identified what looks to be a critical element in the pathogenesis of ALS."

It's no surprise that more work is underway.

* Further study showed that something that entered the medium was the cause, rather than a lack of some protective factor.